Department of Biology, University of Dayton, Dayton, OH, 45469, USA.
Premedical Program, University of Dayton, Dayton, OH, 45469, USA.
Sci Rep. 2018 Sep 10;8(1):13545. doi: 10.1038/s41598-018-31787-7.
Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, also results from accumulation of amyloid-beta 42 (Aβ42) plaques. These Aβ42 plaques trigger oxidative stress, abnormal signaling, which results in neuronal death by unknown mechanism(s). We misexpress high levels of human Aβ42 in the differentiating retinal neurons of the Drosophila eye, which results in the Alzheimer's like neuropathology. Using our transgenic model, we tested a soy-derived protein Lunasin (Lun) for a possible role in rescuing neurodegeneration in retinal neurons. Lunasin is known to have anti-cancer effect and reduces stress and inflammation. We show that misexpression of Lunasin by transgenic approach can rescue Aβ42 mediated neurodegeneration by blocking cell death in retinal neurons, and results in restoration of axonal targeting from retina to brain. Misexpression of Lunasin downregulates the highly conserved cJun-N-terminal Kinase (JNK) signaling pathway. Activation of JNK signaling can prevent neuroprotective role of Lunasin in Aβ42 mediated neurodegeneration. This neuroprotective function of Lunasin is not dependent on retinal determination gene cascade in the Drosophila eye, and is independent of Wingless (Wg) and Decapentaplegic (Dpp) signaling pathways. Furthermore, Lunasin can significantly reduce mortality rate caused by misexpression of human Aβ42 in flies. Our studies identified the novel neuroprotective role of Lunasin peptide, a potential therapeutic agent that can ameliorate Aβ42 mediated neurodegeneration by downregulating JNK signaling.
阿尔茨海默病（AD）是一种致命的进行性神经退行性疾病，也源于淀粉样β 42（Aβ42）斑块的积累。这些 Aβ42 斑块引发氧化应激、异常信号，导致神经元通过未知机制死亡。我们在果蝇眼睛的分化视网膜神经元中过表达高水平的人 Aβ42，导致类似阿尔茨海默病的神经病理学。使用我们的转基因模型，我们测试了一种源自大豆的蛋白质 Lunasin（Lun），以确定其在挽救视网膜神经元神经退行性变中的可能作用。Lunasin 已知具有抗癌作用，并能减轻应激和炎症。我们发现，通过转基因方法过表达 Lunasin 可以通过阻止视网膜神经元的细胞死亡来挽救 Aβ42 介导的神经退行性变，并导致视网膜到大脑的轴突靶向恢复。Lunasin 的过表达下调了高度保守的 cJun-N 末端激酶（JNK）信号通路。JNK 信号的激活可以阻止 Lunasin 在 Aβ42 介导的神经退行性变中的神经保护作用。Lunasin 的这种神经保护功能不依赖于果蝇眼睛中的视网膜决定基因级联，也不依赖于 Wingless（Wg）和 Decapentaplegic（Dpp）信号通路。此外，Lunasin 可以显著降低由人 Aβ42 过表达引起的果蝇死亡率。我们的研究确定了 Lunasin 肽的新的神经保护作用，Lunasin 是一种潜在的治疗剂，通过下调 JNK 信号可以改善 Aβ42 介导的神经退行性变。
